The present invention relates to new analgesic compounds prepared by the hydrolysis of N-acylated 4-hydroxyphenylamine derivatives, the synthesis of these compounds and pharmaceutical compositions containing them. These compounds surprisingly possess high analgesic activity with little hepatotoxic effect, making them more useful than conventional non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of chronic pain.
Analgesics, such as acetaminophen and other NSAIDs, have been used for some time for the treatment of pain. However, the morbidity associated with the hepatotoxic activity means that due care must be exercised when administering these drugs. There are approximately 100,000 cases of acetaminophen overdose annually, with approximately 30 deaths resulting. (Clissold, 1980; McGoldrick et al. 1997). Acetaminophen has a toxic metabolite, N-acetyl-benzoquinoneimine (NAPQI), which depletes hepatic and renal glutathione, a cytoprotective endogenous metabolite (Mason and Fischer, 1986; Mitchell et al., 1983). Hepatic and renal toxicity with acetaminophen can occur at doses only 4- to 8-fold higher than the maximum recommended analgesic dose (Neuberger et al., 1980). Pharmaceutical combinations that contain acetaminophen and a centrally acting analgesic may be even more dangerous than acetaminophen alone. With repeated use these combinations require higher doses to produce the same analgesic effect because of an increase in tolerance. As the dose of the combination is increased to compensate for analgesic tolerance, the safety of the drug decreases as the higher doses of the acetaminophen component increase hepatic and renal toxicity.
In U.S. Pat. No. 5,554,636 (Bazan et al.) and U.S. Pat. No. 5,621,110 (Bazan et al.), two of the inventors herein disclosed the series of N-acylated 4-hydroxyphenylamine derivatives linked via an alkylene bridge to the nitrogen atom of a 1,2-benzisothiazol-3(2H)-one 1,1-dioxide group, referred to as the SCP series, along with the process for their preparation and methods of their use for alleviating pain. The disclosures of these patents are incorporated herein by reference. The SCP series is structurally depicted by the following general formula I: 
wherein n is a number from 1 to 5. These new non-narcotic analgesics surprisingly possess high analgesic activity, do not suppress blood coagulation, and display little hepatotoxic effect.
In addition, in U.S. patent application Ser. No. 10/292,105 (Bazan et al.), the disclosure of which is also incorporated by reference, two of the inventor""s herein also disclosed pharmaceutical combinations, comprising an opioid or a non-opioid analgesic in an intimate admixture with an analgesic from the SCP series, which surprisingly exhibited synergistic analgesia.
In continued search for new, more selective molecules with greater pharmacological potency, it has been ascertained that N-acylated-4-hydroxyphenylamine derivatives, linked via an alkylene bridge to the nitrogen atom of a 2-sulfamoyl benzoic acid group surprisingly possess high analgesic activity and little hepatotoxic effect.
The present invention relates to new analgesic compounds prepared by the hydrolysis of N-acylated 4-hydroxyphenylamine derivatives. The new analgesic compounds have the general formula II: 
in which n is a number between 1 and 5.
Some specific examples of the present invention, without, however, limiting it, are the following:
2-{[(4-hydroxyphenyl)carbamoyl]methylsulfamoyl}benzoic acid;
2-{[(4-hydroxyphenyl)carbamoyl]ethylsulfamoyl}benzoic acid;
2-{[(4-hydroxyphenyl)carbamoyl]proylsulfamoyl}benzoic acid;
2-{[(4-hydroxyphenyl)carbamoyl]butylsulfamoyl}benzoic acid;
2-{[(4-hydroxyphenyl)carbamoyl]pentylsulfamoyl}benzoic acid;
The compounds of general formula II, which are referred to generally as the SCP-M series, may be prepared by the hydrolysis of compounds in the SCP series with 1N aq. NaOH at room temperature, and the product can be purified by recrystallization in ethanol.
The present invention also includes the formation of pharmaceutically acceptable, stable salts of SCP-M series compounds with metals or amines. Examples of metals used in cations are alkali metals such as Na or K and alkaline-earth metals such as Mg and Ca. Examples of amines include N,N-dibenzylethylendiamine, chloroprocaine, choline, diethanolamine, ethylendiamine, N-methylglucamine and procaine.
In addition, the present invention includes pharmaceutical compositions comprising a compound from the SCP-M series in combination with opioid and non-opioid analgesics.